The oncometabolite (R)-2-hydroxyglutarate (R-2-HG) produced by isocitrate dehydrogenase (IDH) mutations promotes gliomagenesis via DNA and histone methylation. Here, we identify an additional activity of R-2-HG: tumor cell–derived R-2-HG is taken up by T cells where it induces a perturbation of nuclear factor of activated T cells transcriptional activity and polyamine biosynthesis, resulting in suppression of T cell activity. IDH1-mutant gliomas display reduced T cell abundance and altered calcium signaling. Antitumor immunity to experimental syngeneic IDH1-mutant tumors induced by IDH1-specific vaccine or checkpoint inhibition is improved by inhibition of the neomorphic enzymatic function of mutant IDH1. These data attribute a novel, non-tumor cell-autonomous role to an oncometabolite in shaping the tumor immune microenvironment.

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We acknowledge the support of the DKFZ Light Microscopy Facility, the microarray unit of the DKFZ Genomics and Proteomics Core Facility, the Transgenic Service of the Center for Preclinical Research, DKFZ, and the DKFZ–Bayer Alliance. We thank the Metabolomics Core Technology Platform of the Excellence Cluster CellNetworks for support with UPLC-based metabolite quantification. The results published here are in part based on data generated by the TCGA Research Network: http://cancergenome.nih.gov/. A2DR1 mice were provided by Institute Pasteur. We thank S. Kircher for flow cytometric analyses; H.Y. Ngyuen, L. Dörner, K. Rauschenbach, and M. Fischer for technical support; and J. Jung for graphics design. This work was supported by the epigenetics@dkfz program to L.B., the DKFZ-MOST program (project number 2526) and the Helmholtz Program Immunology and Inflammation, the Dr. Rolf M. Schwiete Foundation and the German Research Foundation (DFG) (FOR2289: PL315/3-1), the Sonderförderlinie ‘Neuroinflammation’ of the Ministry of Science of Baden Württemberg and the German Ministry of Education and Science (National Center for Tumor Diseases Heidelberg NCT 3.0 program ‘Precision immunotherapy of brain tumors’ and the DKTK program) to M.Pl. the Joint Funding Program MGH-Heidelberg Alliance in Neuro-Oncology to M.Pl. and M.S., the Wilhelm Sander Foundation (2012.118.1) and the German Cancer Aid (70112399) to M.Pl. and A.v.D., the German Cancer Aid (110624) to W.W., the ZUK 49/2 from the DFG to G.P., FOR2289 to B.A.N. and D.A., SFB894 to B.A.N., and the German Cancer Aid to S.T.. L.B. and M.F. are members of the MD/PhD program at Heidelberg University. L.B. was funded by Heidelberg Medical Faculty. T.B., K.S., J.K.S., and M.Ki. are supported by the Helmholtz International Graduate School, T.B. is supported by the Medical Faculty and University Hospital Mannheim. F.S. is supported by a postdoctoral fellowship of the University Hospital Heidelberg. B.W. is supported by the Faculty of Medicine of the Technical University of Munich (KKF grant). E.G. is supported by a Marie-Curie fellowship.

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Author notes

  1. These authors contributed equally: Lukas Bunse, Stefan Pusch, Theresa Bunse.


  1. German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    • Lukas Bunse
    • , Theresa Bunse
    • , Khwab Sanghvi
    • , Mirco Friedrich
    • , Jana K. Sonner
    • , Edward Green
    • , Katrin Deumelandt
    • , Michael Kilian
    • , Anna von Landenberg
    • , Michael O. Breckwoldt
    • , Simone Karcher-Bausch
    • , Iris Oezen
    • , Magdalena Kramer
    •  & Michael Platten
  2. Department of Neurology, Heidelberg University Medical Center, Heidelberg, Germany

    • Lukas Bunse
    • , Tobias Kessler
    • , Wolfgang Wick
    •  & Michael Platten
  3. National Center for Tumor Diseases Heidelberg, DKTK, Heidelberg, Germany

    • Lukas Bunse
    • , Theresa Bunse
    • , Tobias Kessler
    • , Wolfgang Wick
    •  & Michael Platten
  4. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany

    • Lukas Bunse
    • , Khwab Sanghvi
    • , Katrin Deumelandt
    • , Michael Kilian
    •  & Andreas von Deimling
  5. Department of Neuropathology, Heidelberg University Medical Center, Heidelberg, Germany

    • Stefan Pusch
    • , Felix Sahm
    • , Jochen Meyer
    • , Antje Habel
    • , Jessica Eisel
    • , Daniel Schrimpf
    •  & Andreas von Deimling
  6. DKTK CCU Neuropathology, DKFZ, Heidelberg, Germany

    • Stefan Pusch
    • , Felix Sahm
    • , Jochen Meyer
    • , Antje Habel
    • , Jessica Eisel
    •  & Daniel Schrimpf
  7. Department of Neurology, University Hospital and Medical Faculty Mannheim, Mannheim, Germany

    • Theresa Bunse
    •  & Michael Platten
  8. Molecular Biophysics, Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, Germany

    • Dalia Alansary
    •  & Barbara A. Niemeyer
  9. Broad Institute of Harvard and MIT and Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    • Cyril Neftel
    •  & Mario L. Suvà
  10. FlowCore Mannheim and Institute of Transfusion Medicine and Immunology, Mannheim, Germany

    • Stefanie Uhlig
    •  & Karen Bieback
  11. DKTK CCU Neurooncology, DKFZ, Heidelberg, Germany

    • Tobias Kessler
    • , Anna S. Berghoff
    • , Miriam Ratliff
    •  & Wolfgang Wick
  12. Institute of Neurology, Medical University of Vienna, Vienna, Austria

    • Anna S. Berghoff
  13. CNS Tumors Unit, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

    • Anna S. Berghoff
    •  & Matthias Preusser
  14. Agios Pharmaceuticals, Inc., Cambridge, MA, USA

    • Kelly Marsh
    • , Mya Steadman
    • , Dongwei Zhu
    • , Brandon Nicolay
    •  & Marion Dorsch
  15. Department of Diagnostic and Interventional Neuroradiology, Neuro-Kopf-Zentrum, Klinikum rechts der Isar, Technical University Munich, Munich, Germany

    • Benedikt Wiestler
  16. Department of Neuroradiology, Heidelberg University Medical Center, Heidelberg, Germany

    • Michael O. Breckwoldt
  17. Max Eder Junior Group on Low Grade Gliomas, Heidelberg University Medical Center, Heidelberg, Germany

    • Ruslan Al-Ali
    •  & Sevin Turcan
  18. DNA Vectors Unit, DKFZ, Heidelberg, Germany

    • Matthias Bozza
    •  & Richard Harbottle
  19. Center for Organismal Studies, University Heidelberg, Heidelberg, Germany

    • Gernot Poschet
  20. Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland

    • Michael Weller
  21. Department for Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria

    • Matthias Preusser
  22. Department of Neurosurgery, Stuttgart Clinics, Stuttgart, Germany

    • Minou Nadji-Ohl
  23. Department of Neurosurgery, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany

    • Niklas Thon
  24. Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, Frankfurt, Germany

    • Michael C. Burger
  25. DKTK Partner Site Frankfurt/Mainz, Frankfurt, Germany

    • Michael C. Burger
    • , Patrick N. Harter
    •  & Karl H. Plate
  26. Institute of Neurology (Edinger Institute), University Hospital and Medical Faculty, Goethe University, Frankfurt, Germany

    • Patrick N. Harter
    •  & Karl H. Plate
  27. Neurosurgery Clinic, University Hospital Mannheim, Mannheim, Germany

    • Miriam Ratliff
    •  & Daniel Hänggi
  28. Division of Biostatistics, DKFZ, Heidelberg, Germany

    • Axel Benner
  29. Metabolic Center Heidelberg, University Children’s Hospital, Heidelberg, Germany

    • Jürgen Okun
  30. Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Medical Center, Heidelberg, Germany

    • Christel Herold-Mende
  31. Research and Development, Pharmaceuticals, Bayer AG, Berlin, Germany

    • Stefan Kaulfuss
    •  & Holger Hess‐Stumpp
  32. Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    • Daniel P. Cahill


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L.B., S.P., and T.B. designed and performed experiments, analyzed data, and wrote the paper. F.S. and A.v.D. provided glioma tissue, determined IDH1 status, provided tissue stainings, and performed 850 k methylation arrays. K.S., M.F., M.Ki., A.v.L., and S.K.-B. performed in vitro experiments. J.K.S., M.Kr., and I.O. performed in vivo experiments. D.A. and B.A.N. performed calcium and respiration measurements. E.G., M.B., and R.H. performed genetic modification of cell lines. K.D. analyzed primary human tissue. C.N., M.L.S., S.U., and K.B. were involved in TIL processing. T.K. and D.S. analyzed RNA-seq data. A.S.B. and M.Pr. provided glioma tissue, determined IDH1 status, and provided immunohistochemistry stainings. K.M., M.S., D.Z., B.N., and M.D. performed metabolomics and interpreted data. B.W. performed statistical and TCGA analyses. M.O.B. performed magnetic resonance imaging. R.A.-A. and S.T. performed epigenetic profiling. J.M. and A.H. performed RNA-seq. G.P. performed adenosine phosphate and polyamine measurements. M.W. provided glioma tissues and was involved in data interpretation. M.N.-O., N.T., M.C.B., P.N.H., M.R., D.P.C., K.H.P., and D.H. provided glioma tissue. A.B. performed KEGG pathway analyses. J.E. and J.O. performed R-2-HG measurements. C.H.-M. provided the primary glioma cell line. S.K. and H.H.-S. interpreted data and provided BAY1436032. W.W. was involved in study design and data interpretation. M.Pl. conceptualized the study, interpreted data, and wrote the paper.

Competing interests

M.Pl., W.W., and T.B. are inventors on a patent application entitled ‘Means and methods for treating or diagnosing IDH1R132H mutant-positive cancers’ (WO 2013/102641 A1, PCT/EP2013/050048). S.P. and A.v.D. are eligible to royalties as co-inventors of BAY 1436032 and are patent holders of ‘Means and methods for the determination of (D)-2-hydroxyglutarate (D2HG)’ (WO2013127997A1). This patent is under the administrative supervision of the DKFZ technology transfer office. K.M., M.S., D.Z., B.N., and M.D. are full-time employees of Agios. S.K. and H.H.S. are full-time employees of Bayer. The other authors declare no conflict of interest. Requests for materials should be addressed to m.platten@dkfz.de.

Corresponding author

Correspondence to Michael Platten.

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